Radiation therapy (RT) is commonly used to treat solid tumors~ however, even with sophisticated treatment planning and dose delivery, the local control for many cancers remains poor. One clear example is high-risk (human papilloma virus (HPV)-negative), locally-advanced head and neck squamous cell carcinoma (LA-HNSCC), where local recurrences are common and cause significant morbidity and death. One factor strongly associated with local recurrence following RT in LA-HNSCC is tumor hypoxia. Consistent with this, hypoxia modification has been shown to improve local control and overall survival in patients with HNSCC, particularly in those with HPV-negative disease. We have found in pre-clinical models that nelfinavir (NFV), a HIV protease inhibitor with a long history of use in the clinic, decreases tumor hypoxia, which may increase extrinsic radiosensitivity. Additionally, NFV increases intrinsic radiosensitivity, as measured by clonogenic survival assays. We hypothesize that this may be related to the drug's ability to decrease glucose uptake. Aim 1 is a phase II clinical trial of NFV in combination with RT and concurrent cisplatin chemotherapy for patients with HPV-negative, locally advanced larynx cancer, which has a poor prognosis with standard chemoradiation. Outcomes will be compared to historical controls receiving standard therapy (5-yr disease- free survival 40%) to determine whether there is any improvement with the addition of NFV. We will assess the effect of NFV on hypoxia and tumor glucose metabolism via 18F-EF5 and 18F-FDG PET/CT scanning, respectively. We will measure the effect of NFV on the PI3K/Akt pathway by assessing phosphorylation of Akt and downstream proteins in peripheral blood mononuclear cells (PBMC). Correlation between clinical outcome and response via imaging or PBMCs may allow us to predict which patients are likely to respond to NFV, and to enrich our population for a future phase III randomized trial. Our approach may lead to a novel approach to treating HNSCC with radiation, which could be extended to other cancer types treated primarily with radiation. In the subsequent aims we will investigate two aspects of NFV action that are highly relevant to the ideas being tested in the clinical trial in Aim 1. In Aim 2 we will determine whether the effect of NFV on O2 consumption is mediated by Akt inhibition and whether the drug affects mitochondria function. If we find that the O2 effect is mediated by Akt, then measuring changes in hypoxia may be a surrogate for measuring Akt inhibition in this setting. In Aim 3, we will determine whether the effect of NFV on decreasing glucose uptake is mediated by Akt inhibition, which would have implications for using 18F-FDG-PET/CT scanning to assess the efficacy of PI3K/Akt inhibitors in general. We will also investigate whether the decrease in glucose uptake in response to NFV leads to impaired anti-oxidant capacity by decreasing flux through the oxidative pentose phosphate cycle (OPPC), which we hypothesize contributes to the drug's ability to increase intrinsic radiosensitization.